This invention relates to a new use of inhibitors of bacterial xcex2-lactamases. More particularly, this invention is directed to the use of xcex2-lactamase inhibitors for preventing or reducing neuronal damage in patients suffering from or susceptible to disease states characterized by loss of neuronal cells or loss of neuronal cell function.
Over excitation of NMDA receptor channel complexes on post-synaptic neurons following excessive release of glutamic acid from synaptozones and glial cells results in massive calcium ion influx into neuronal cells leading to their death. This is believed to occur under conditions such as stroke, hypoglycemia, cardiac arrest, and other hypoxic or ischemic processes, including, for example, neural trauma, and perinatal asphyxia. Other conditions known to result in or from loss of neuronal cells or loss of neuronal function include seizure activity such as that associated with epilepsy, amyliotrophic lateral sclerosis (ALS), Alzheimer""s disease, Huntington""s disease, Parkinsonism and dementia such as multi-infarct dementia, vascular dementia, and neurodegenerative dementia. Other conditions known to result in loss of neuronal cells or loss of neuronal cell function are those generally characterized as secondary neurodegenerative disease of typically metabolic or toxic origin. While significant progress has been made in developing therapeutics for treatment or prevention of such neurodegenerative conditions or disease states, there still exists significant need for the development of alternative therapies for treatment of patients afflicted with such conditions.
Accordingly, the present invention provides a surprisingly effective neuroprotective therapy. It is based on the discovery that compound capable of inhibiting the activity of bacterial xcex2-lactamases (i.e., xcex2-lactamase inhibitors) is, as well, a powerful neuroprotective agent. The invention thus provides a method for preventing neuronal damage or the progression of neuronal damage in a patient suffering from or susceptible to said damage, characterized generally as a loss of neuronal cells or a loss of neuronal cell function, such as that secondary to the occurrence of strokes, seizures, neural trauma, and a multiplicity of neuro-degenerative disease states of widely variant etiology.
In another embodiment of the invention there is provided a neuroprotective pharmaceutical composition and a method for manufacturing same using a xcex2-lactamase inhibitor as the active ingredient. Such pharmaceutical compositions can be formulated in unit dosage forms adapted for patient delivery by a wide variety of routes of administration including, but not limited to, oral ingestion, buccal, sublingual, parenteral, transdermal and rectal routes of administration. In one embodiment the dosage forms are formulated for controlled release of the xcex2-lactamase inhibitor.